In recent years, the pathology of diabetes has become more well understood and, in parallel, drugs specific for the respective pathologic states have been developed. Accordingly, a variety of drugs having new mechanisms of action have appeared one after another.
Insulin sensitivity enhancers are also known as insulin resistance deblockers because they have the action of normalizing the impaired insulin receptor function, and are gathering much attention in these years.
Regarding such insulin sensitivity enhancers, a very useful compound such as pioglitazone has been developed [Fujita et al., Diabetes, 32, 804-810, 1983, JP-A S55(1980)-22636 (EP-A 8203), JP-A S61(1986)-267580 (EP-A 193256)]. Pioglitazone restores the impaired insulin receptor function to normalize the uneven distribution of glucose transporters in cells, the cardinal enzyme systems associated with glycometabolism, such as glucokinase, and enzyme systems associated with lipid metabolism, such as lipoprotein lipase. As a result, insulin resistance is deblocked to improve glucose tolerance, and lower the plasma concentrations of neutral lipids and free fatty acids. Since these actions of pioglitazone are comparatively gradual and the risk of side effects in long-term administration is also low, this compound is useful for obese patients who are presumed to be highly insulin-resistant.
Also, insulin sensitivity enhancers such as CS-045, thiazolidinedione derivatives and substituted thiazolidinedione derivatives are reported to be used in combination with insulin [JP-A H4(1992)-66579, JP-A H4(1992)-69383, JP-A H5(1993)-202042]. However, the pharmaceutical composition having a specific combination of the present invention is unknown.
Diabetes is a chronic disease with diverse pathologic manifestations and is accompanied by lipid metabolism disorders and circulatory disorders as well as glycometabolism disorders. As a result, diabetes tends to progress involving various complications in many cases. Therefore, it is necessary to select the drug of choice for the prevailing disease state in each individual case. However, this selection is often difficult in clinical settings because single use of each individual drug can not bring sufficient effects in some disease states and there are various problems such as side effect which is caused by an increased dose or a long-term administration.